Multi Targeted Therapy for Alzheimer's Disease by Guanidinium-Modified Calixarene and Cyclodextrin Co-Assembly Loaded with Insulin.

Amyloid-β (Aβ) is considered a primary therapeutic target for Alzheimer's disease (AD). However, just eliminating Aβ in patients with AD has exhibited restricted clinical efficacy, possibly failing to address the metabolic abnormalities caused by AD, such as insulin resistance. To address this concern, our research has employed two types of macrocyclic amphiphiles, guanidinium-modified calixarene and cyclodextrin coassembly (GCD), as delivery systems for insulin. This approach aimed to tackle the metabolic dysregulation characteristic of AD in an innovative manner by exploring beyond the conventional strategy of Aβ removal. As a result, GCD and insulin coassembly could effectively improve plaque deposition and insulin resistance. The coassembly could also reduce abnormal neuronal apoptosis and synaptic damage and improve cognitive impairment in 5xFAD mice. Therefore, the GCD and insulin coassembly shows promise as a viable therapeutic option for AD.